Prevalence and Characterization of Biallelic and Monoallelic <i>NTHL1</i> and <i>MSH3</i> Variant Carriers From a Pan-Cancer Patient Population.

Abstract

<i>NTHL1</i> and <i>MSH3</i> have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic <i>NTHL1</i> and <i>MSH3</i> pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize <i>NTHL1</i> and <i>MSH3</i> from a large pan-cancer patient population. Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database). <i>NTHL1</i>-PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. <i>NTHL1</i>-associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any <i>NTHL1</i> patient. <i>MSH3</i>-PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic <i>MSH3</i> variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 <i>MSH3</i> carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type <i>MSH3</i> allele. Ancestry-specific burden tests demonstrated that <i>NTHL1</i> and <i>MSH3</i> prevalence was not significantly different in this pan-cancer population versus controls. <i>NTHL1</i> and <i>MSH3</i> germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.